Alzheimer's disease (AD) is the most common form of senile dementia. An estimated 5.3 million Americans are affected, and this number is increasing yearly. Currently, there is no cure for AD; however, it is widely accepted that inhibiting amyloid plaque formation would be beneficial for the prevention of Alzheimer's disease. Although there are many approaches for the treatment of AD, one novel and innovative approach is to modulate the activity of the key enzyme complex involved in Abeta42 production (a primary component of amyloid plaques), gamma-secretase. Because of the potential for serious side-effects associated with inhibition of gamma-secretase, modulation of its activity was targeted in order to avoid non-specific effects on other gamma-secretase substrates such as the Notch, an essential element for normal cellular development. Our scientific approach utilized a cell-based assay that led to the discovery of a proprietary series of gamma-secretase modulators. Medicinal chemistry followed by in vitro and in vivo optimization efforts led to the identification of the lead compound NGP 328, a small molecule that has been demonstrated to lower Abeta42 both in vitro and in vivo and which promotes the formation of smaller, potentially less toxic Abeta peptides (Abeta37 and Abeta38) without altering the activity of gamma-secretase toward other substrates such as Notch. We propose to do an initial proof of concept study in a non-transgenic rodent in which initial toxicity and safety studies will be conducted. We plan to compare the effects of orally delivered NGP 555 on specific Abeta biomarkers in rat CSF to any Notch-related toxicity to determine a therapeutic window. Additionally, we will identify an appropriate oral or solid delivery system for future toxicity and safety studies. If these studies are successful, we plan to initiate full-fledged pre- clinical development of NGP 555 for the prevention of Alzheimer's disease. In this proposal we plan to identify a therapeutic window for modulating Abeta peptides in rodent CSF to Notch-related histological toxicity (proof of concept study) and to complete pre-clinical development of NGP 555 including the following: 1) Prepare a batch of non-GMP NGP 555 drug substance to support nonclinical studies. 2) Conduct IND-enabling beagle dog cardiopulmonary safety, acute toxicity, and 14-day toxicity studies. 3) Conduct in vivo NGP 555 genotoxicity, drug elimination and tissue distribution studies and conduct drug-drug interaction studies in vitro. These studies are expected to result in filing an Investigational New Drug (IND) application for NGP 555.